Process for preparing 4-substituted piperidines

ABSTRACT

The present invention provides a process for preparing N-protected-4-substituted piperidines of formula (I) wherein Pg represents a suitable nitrogen protecting group; X represents a heterocycle, substituted heterocycle, substituted alkenyl or substituted aryl wherein the substituted heterocycle, substituted alkenyl or substituted aryl are substituted with from 1 to 3 suitable activating groups; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  each independently represent an alkyl, alkenyl, cycloalkyl, aryl, substituted aryl, heterocycle, or substituted heterocycle, comprising treating a compound of formula (II) wherein the substituents are defined as above, with triethylsilane and trifluoroacetic acid.

[0001] The present invention allows for the selective reduction of atertiary alcohol on an N-protected-4-substituted piperidine without theconcomitant deprotection of the protected piperidine nitrogen. Theinvention further allows for subsequent deprotection of theN-protected-4-substituted piperidine in one pot without isolation of theintermediate reduced compound. Thus, the present invention provides anefficient synthesis of various 4-substituted piperidines which areuseful intermediates in the preparation of pharmaceuticals.

[0002] The present invention provides a process for preparing a reducedN-protected amine compound comprising reducing an N-protected aminepossessing a secondary or tertiary alcohol with triethylsilane andtrifluoroacetic acid

[0003] The present invention further provides a process for preparing anN-protected-4-substituted piperidine comprising treating anN-protected-4-substitued piperidine having a tertiary alcohol at the4-position of the piperidine ring with triethylsilane andtrifluoroacetic acid.

[0004] In addition, the present invention provides a process forpreparing a compound of formula I:

[0005] wherein Pg represents a suitable nitrogen protecting group;

[0006] X represents a heterocycle, substituted heterocycle, substitutedalkenyl or substituted aryl wherein the substituted heterocycle,substituted alkenyl or substituted aryl are substituted with from 1 to 3suitable activating groups; and

[0007] R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ each independently representan alkyl, alkenyl, cycloalkyl, aryl, substituted aryl, heterocycle, orsubstituted heterocycle, comprising treating a compound of formula II:

[0008] wherein the substituents are defined as above, withtriethylsilane and trifluoroacetic acid.

[0009] As used herein the term “reduced N-protected amine compound”refers to a compound possessing an amine functionality that is protectedwith a suitable acid labile nitrogen protecting group, and any secondaryor tertiary alcohol functionality has been replaced by a hydrogen atom.For example, see equation 1

[0010] wherein

[0011] Q represents a secondary or tertiary alcohol, and the symbol;

[0012]  represents any suitable chemical substrate.

[0013] As used herein the term “suitable chemical substrate” refers tothe remaining portion of the entire compound (a) or (b) above which doesnot include substituents “Q” or “PgHN—”, and which will not react withtriethylsilane in the presence of trifluoroacetic acid unless suchadditional reaction is desired.

[0014] As used herein the piperidine of formulas I, Ia, and II have thefollowing numbering system for the piperidine ring using formula I as anexample:

[0015] As used herein, the terms “Me”, “Et”, “Pr”, “iPr”, “Bu” and“t-Bu” refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butyl,respectively.

[0016] As used herein, the terms “Halo”, “Halide” or “Hal” refer to achlorine, bromine, iodine or fluorine atom, unless otherwise specifiedherein.

[0017] As used herein the term “alkyl” refers to a straight or branched,monovalent, saturated aliphatic chain. It is understood that the term“alkyl” includes within its definition the terms “C₁-C₂₀ alkyl”, “C₁-C₁₀alkyl”, “C₁-C₆ alkyl”, and “C₁-C₄ alkyl”.

[0018] As used herein the term “C₁-C₄ alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 4 carbon atomsand includes, but is not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl and the like.

[0019] As used herein the term “C₁-C₆ alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 6 carbon atomsand includes, but is not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0020] As used herein the term “C₁-C₁₀ alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 10 carbon atomsand includes, but is not limited to methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl,2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl,octyl, 4-methyl-3-heptyl and the like.

[0021] As used herein the term “C₁-C₂₀ alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 20 carbon atomsand includes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl,2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl,n-nonadecyl, n-eicosyl and the like.

[0022] As used herein the term “C₁-C₆ alkoxy” refers to a straight orbranched alkyl chain having from one to six carbon atoms attached to anoxygen atom. Typical C₁-C₆ alkoxy groups include methoxy, ethoxy,propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term“C₁-C₆ alkoxy” includes within its definition the term “C₁-C₄ alkoxy”.

[0023] As used herein the term “halo(C₁-C₆)alkyl” refers to a straightor branched alkyl chain having from one to six carbon atoms with 1, 2 or3 halogen atoms attached to it. Typical halo(C₁-C₆)alkyl groups includechloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl,2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl andthe like. The term “halo(C₁-C₆)alkyl” includes within its definition theterm “halo(C₁-C₄)alkyl”.

[0024] As used herein the term “cycloalkyl” refers to a saturatedhydrocarbon ring structure. It is understood that the term “cycloalkyl”includes within its definition the term “C₃-C₈ cycloalkyl”. TypicalC₃-C₈ cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0025] As used herein the term “alkenyl” refers to a straight orbranched, monovalent, unsaturated aliphatic chain. It is understood thatthe term “alkenyl” includes within its definition the term “C₂-C₆alkenyl”. Typical C₂-C₆ alkenyl groups include ethenyl (also known asvinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl,2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, andthe like.

[0026] As used herein the term “aryl” refers to a monovalent carbocyclicgroup containing one or more fused or non-fused phenyl rings andincludes, for example, phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and the like.

[0027] As used herein the term “heterocycle” refers to a stable 5- to7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ringwhich is saturated or unsaturated, and consists of carbon atoms and fromone to three heteroatoms selected from the group consisting of nitrogen,oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms mayoptionally be oxidized, and the nitrogen heteroatom may optionally bequaternized and including a bicyclic group in which any of theabove-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any heteroatom or carbon atom whichaffords a stable structure.

[0028] Examples of such heterocycles include piperidinyl, piperazinyl,azepinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl,morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl,thiadiazolyl, benzopyranyl, benzothiazolyl, benzoazolyl, furyl,tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl,thiamorpholinyl, thiamorpholinyl-sulfoxide, thiamorpholinylsulfone,oxadiazolyl, triazolyl, tetrahydroquinolinyl, tetrahydrisoquinolinyl,and the like.

[0029] Unless otherwise specified, the term “substituted” as used in theterm “substituted alkenyl”, “substituted aryl” and “substitutedheterocycle” signifies that one or more (for example one or two)substituents may be present on the alkenyl, aryl or heterocycle.Examples of substituents which may be present are H, F, Cl, Br, I, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halo(C₁-C₆)alkyl, phenyl, NO₂. NH₂, CN, orphenyl substituted with from 1 to 3 substituents selected from the groupconsisting of F, Cl, Br, I, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy,halo(C₁-C₆)alkyl, phenyl, NO₂, NH₂, and CN.

[0030] When X represents substituted aryl or substituted heterocycle, itis preferred that the substituted aryl or substituted heterocycle do notcontain an electron withdrawing substituent.

[0031] More specifically, when X represents a substituted heterocycle,substituted alkenyl or substituted aryl, the substituted heterocycle,substituted alkenyl or substituted aryl is substituted with from 1 to 3suitable activating groups, such as substituents which are electrondonating. Examples of suitable activating groups are OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, phenyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)₂, and thelike.

[0032] The designation “

” refers to a bond that protrudes forward out of the plane of the page.

[0033] The designation “

” refers to a bond that protrudes backward out of the plane of the page.

[0034] As used herein, the term “stereoisomer” refers to a compound madeup of the same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. In addition, two diastereomers which have a differentconfiguration at only one chiral center are referred to herein as“epimers”. The terms “racemate”, “racemic mixture” or “racemicmodification” refer to a mixture of equal parts of enantiomers.

[0035] The term “enantiomeric enrichment” as used herein refers to theincrease in the amount of one enantiomer as compared to the other. Aconvenient method of expressing the enantiomeric enrichment achieved isthe concept of enantiomeric excess, or “ee”, which is found using thefollowing equation:${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$

[0036] wherein E¹ is the amount of the first enantiomer and E² is theamount of the second enantiomer. Thus, if the initial ratio of the twoenantiomers is 50:50, such as is present in a racemic mixture, and anenantiomeric enrichment sufficient to produce a final ratio of 50:30 isachieved, the ee with respect to the first enantiomer is 25%. However,if the final ratio is 90:10, the ee with respect to the first enantiomeris 80%. An ee of greater than 90% is preferred, an ee of greater than95% is most preferred and an ee of greater than 99% is most especiallypreferred. Enantiomeric enrichment is readily determined by one ofordinary skill in the art using standard techniques and procedures, suchas gas or high performance liquid chromatography with a chiral column.Choice of the appropriate chiral column, eluent and conditions necessaryto effect separation of the enantiomeric pair is well within theknowledge of one of ordinary skill in the art. In addition, theenantiomers of compounds of formulas I or Ia can be resolved by one ofordinary skill in the art using standard techniques well known in theart, such as those described by J. Jacques, et al., “Enantiomers,Racemates, and Resolutions”, John Wiley and Sons, Inc., 1981.

[0037] Some of the compounds of the present invention have one or morechiral centers and may exist in a variety of stereoisomericconfigurations. As a consequence of these chiral centers, the compoundsof the present invention occur as racemates, mixtures of enantiomers andas individual enantiomers, as well as diastereomers and mixtures ofdiastereomers. All such racemates, enantiomers, and diastereomers arewithin the scope of the present invention.

[0038] The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in “Nomenclature of Organic Compounds:Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages103-120.

[0039] The specific stereoisomers and enantiomers of compounds offormula (I) can be prepared by one of ordinary skill in the artutilizing well known techniques and processes, such as those disclosedby Eliel and Wilen, “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, Chapter 7, Separation of Stereoisomers. Resolution.Racemization, and by Collet and Wilen, “Enantiomers, Racemates, andResolutions”, John Wiley & Sons, Inc., 1981. For example, the specificstereoisomers and enantiomers can be prepared by stereospecificsyntheses using enantiomerically and geometrically pure, orenantiomerically or geometrically enriched starting materials. Inaddition, the specific stereoisomers and enantiomers can be resolved andrecovered by techniques such as chromatography on chiral stationaryphases, enzymatic resolution or fractional recrystallization of additionsalts formed by reagents used for that purpose.

[0040] As used herein, “Pg” refers to suitable nitrogen protecting groupsuch as an acid labile nitrogen protecting group. Examples of an acidlabile nitrogen protecting group as used herein refers to those groupsintended to protect or block the nitrogen group against undesirablereactions during synthetic procedures, whereby the basicity of the aminefunctionality is significantly reduced. Choice of the suitable nitrogenprotecting group used will depend upon the conditions that will beemployed in subsequent reaction steps wherein protection is required,and is well within the knowledge of one of ordinary skill in the art.Commonly used nitrogen protecting groups are disclosed in Greene,“Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York(1981)). Acid labile carbamates are most suitable such as the followingderivatives: 3,4-dimethoxybenzyloxycarbonyl,3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dlimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, allyloxycarbonyl, 2-methyl-but-2-enyloxycarbonyl,2,3-dimethyl-but-2-enyloxycarbonyl. Preferred acid labile nitrogenprotecting groups are, t-butyloxycarbonyl (Boc) and3,4,5-trimethoxybenzyloxycarbonyl. t-Butyloxycarbonyl (Boc) is the mostpreferred suitable nitrogen protecting group.

[0041] The compounds of formulas I and Ia can be prepared by followingthe procedures as set forth in Scheme I. All substituents, unlessotherwise indicated, are previously defined. The reagents and startingmaterials are readily available to one of ordinary skill in the art.

[0042] In Scheme I, step A, the compound of formula II is dissolved in asuitable organic solvent, such as methylene chloride and treated withabout 4 equivalents to about 5 equivalents of triethylsilane, preferablyabout 5 equivalents of triethylsilane. The solution is cooled to about−40° C. to about −25° C., preferably about −30° C. The solution is thentreated slowly with about 4 equivalents to about 5 equivalents oftrifluoroacetic acid, preferably about 5 equivalents of trifluoroaceticacid. The reaction is then allowed to warm to about 0-5° C. over about30 minutes to about one hour with stirring. The product, formula I, isthen isolated and purified by standard techniques well known in the art,such as extraction techniques and chromatography. For example, thereaction mixture is treated with ice water and aqueous sodium hydroxidewith stirring. The layers are separated and the aqueous layer isextracted with methylene chloride. The organic layer and extracts arecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to provide the crude compound of formula I.This crude material can then be purified by flash chromatography onsilica gel with a suitable eluent, such as ethyl acetate/hexanes.

[0043] In Scheme I, step B, the compound of formula I can be deprotedtedunder standard conditions well known in the art, such as those disclosedin Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons,New York (1981)), to provide the compound of formula la. For example,the compound of formula I is dissolved in a suitable organic solvent,such as methylene chloride, the solution is cooled to about 0° C., andtreated with an excess of trifluoroacetic acid. The reaction mixture isallowed to stir for about 2 to 8 hours and the product, formula la, isthen isolated and purified by using standard techniques well known inthe art. For example, the reaction is treated with ice water and aqueoussodium hydroxide with stirring. The layers are separated and the aqueouslayer is extracted with methylene chloride. The organic layer andorganic extracts are combined, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum to provide the crude material offormula Ia. This crude material can then be purified by flashchromatography on silica gel with a suitable eluent, such as ethylacetate/hexanes.

[0044] In Scheme I, step C, the compound of formula I is dissolved in asuitable organic solvent, such as methylene chloride and treated withabout 4 equivalents to about 5 equivalents of triethylsilane, preferablyabout 5 equivalents of triethylsilane. The solution is cooled to about−40° C. to about −25° C., preferably about −30° C. The solution is thentreated slowly with about 4 equivalents to about 5 equivalents oftrifluoroacetic acid, preferably about 5 equivalents of trifluoroaceticacid. The reaction is then allowed to warm to about 0-5° C. over about30 minutes to about one hour with stirring, and an additional 4 to 5equivalents of trifluoroacetic acid is added. The reaction is thenallowed to warm to room temperature, and the product, formula Ia, isisolated and purified by standard techniques well known in the art, suchas extraction techniques and chromatography. For example, the reactionmixture is treated with ice water and aqueous sodium hydroxide withstirring. The layers are separated and the aqueous layer is extractedwith methylene chloride. The organic layer and extracts are combined,dried over anhydrous sodium sulfate, filtered, and concentrated undervacuum to provide the crude compound of formula Ia. This crude materialcan then be purified by flash chromatography on silica gel with asuitable eluent, such as ethyl acetate/hexanes.

[0045] The following examples are illustrative only and representtypical syntheses of the compounds of formula I as described generallyabove. The reagents and starting materials are readily available to oneof ordinary skill in the art. As used herein, the following terms havethe meanings indicated: “eq” or “equiv.” refers to equivalents; “g”refers to grams; “mg” refers to milligrams; “L” refers to liters; “mL”refers to milliliters; “μL” refers to microliters; “mol” refers tomoles; “mmol” refers to millimoles; “psi” refers to pounds per squareinch; “min” refers to minutes; “h” refers to hours; “° C.” refers todegrees Celsius; “TLC” refers to thin layer chromatography; “HPLC”refers to high performance liquid chromatography; “R_(f)” refers toretention factor; “R_(t)” refers to retention time; “δ” refers to partsper million down-field from tetramethylsilane; “THF” refers totetrahydrofuran; “DMF” refers to N,N-dimethyiformamide; “DMSO” refers tomethyl sulfoxide; “LDA” refers to lithium diisopropylamide; “aq” refersto aqueous; “EtOAc” refers to ethyl acetate; “iPrOAc” refers toisopropyl acetate; “MeOH” refers to methanol; “MTBE” refers totert-butyl methyl ether, and “RT” refers to room temperature.

Preparation 1

[0046] Preparation of5-Bromo-3-methyl-1-trimethylsilylbenzo[b]thiophene.

[0047] A solution of 5-bromo-3-methylbenzo[b]thiophene (149.1 g, 0.66mole) in THF (1.4 L) under nitrogen was cooled to −78° C. andtrimethylsilyl chloride (163 mL, 1.3 mole, 2 eq) was added dropwise.Lithium diisopropylamide (625 mL, 1.2 mole, 2 eq, 2.0 M solution in THF,heptane, ethylbenzene) was added and the mixture was stirred for 4 h.The solution was poured into a mixture of methyl tert-butylether and H₂O(3 L each). The layers were separated and the organic layer wasextracted with 1 N HCl (2 L), then H₂O (2 L) and dried (Na₂SO₄). Thesolvent was removed by rotary evaporation to afford 237.3 g of crudeproduct. The crude material was slurried in EtOH (400 mL) to afford5-bromo-3-methyl-1-trimethylsilylbenzo[b]thiophene as a white granularsolid (152.7 g, 78%, 3 crops).

[0048] mp64-67° C. IR (KBr) 1252, 1245, 841 cm⁻¹;

[0049]¹H NMR (300 MHz, CDCl₃) δ 7.851 (d, 1, J=1.8 Hz), 7.69 (d, 1,J=8.5 Hz), 7.41 (dd, 1, J=8.5, 1.8 Hz), 2.48 (s, 3,), 0.42 (d, 9, J=3.4Hz). ¹³CNMR (75 MHz, CDCl₃) δ 143.6, 141.3, 137.9, 132.2, 126.9, 124.4,123.4, 117.8, 14.4, 0.14. MS (FD) m/z 298 (M+). Anal. Calcd forC₁₀H₁₅BrSSi: C, 48.16; H, 5.05. Found: C, 48.19; H, 4.98.

Preparation 2

[0050] Preparation of1-(t-Butyloxycarbonyl)-4-(3-methylbenzo[b]thiophen-5-yl)-piperidin-4-ol.

[0051] To a solution of5-bromo-3-methyl-1-trimethylsilylbenzo[b]thiophene (211.7 g, 707 mmol)in THF (1 L) cooled to −78° C. under nitrogen was added n-BuLi (311 mL,2.5 M solution in hexanes, 778 mmol) dropwise. After 30 min,N-Boc-piperidone (155.1 g, 778 mmol) in THF (816 mL) was added. After 2hr, the mixture was poured into H₂O and methyl tert-butylether (2 Leach). The layers were separated and the organic layer was washed with 1N HCl (2.1 L), then H₂O (2.1 L) and dried (Na₂SO₄). The solvent wasremoved with a rotary evaporator to afford 348 g of crude1-(t-butyloxycarbonyl)-4-(3-methyl-1-trimethylsilylbenzo[b]thiophen-5-yl)-piperidin-4-ol.Hexane (700 mL) was added to the crude product. After stirringovernight, the precipitate was filtered, washed with hexane, and driedin a vacuum oven for 2 hr to give 246.3 g (83%) of1-(t-butyloxycarbonyl)4-(3-methyl-1-trimethylsilylbenzolblthiophen-5-yl)-piperidin-4-olas a white powder. mp 141-145° C. IR (CHCl₃) 3595, 1680 cm⁻¹.

[0052]¹H NMR (300 MHz, CDCl₃), δ 7.83 (d, 1, J=8.0 Hz), 7.81 (s, 1),7.43 (dd, 1, J=8.2, 1.8 Hz), 4.06 (br s, 2), 3.28 (t, 2, J=12.2 Hz),2.51 (s, 3), 2.09 (br s, 2), 1.79 (d, 2, J=12.2 Hz), 1.70 (s, 1), 1.49(s, 9), 0.40 (s, 9). ¹³C NMR (75 MHz, DMSO) δ 154.2, 145.9, 141.5,140.3, 139.1, 134.1, 122.2, 121.8, 117.7, 78.6, 70.2, 38.0, 28.3, 14.4,0.00. MS (FD) m/z 418 (M−1). Anal. Calcd for C₂₂H₃₃NO₃SSi: C, 62.97; H,7.93; N, 3.34. Found: C, 63.28; H, 8.04; N, 3.44.

Preparation 3

[0053] Preparation of (±)N-t-Butoxycarbonyl-4-hydroxy-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine.

[0054] To a solution of 6-methoxybenzo[b]thiophene (5.0 g, 30.4 mmol) indry THF (60 mL) at −78° C. was added 1.6 M n-BuLi in hexanes (20.9 mL,33.44 mmol). The solution was stirred at −78° C. for 90 min. TheN-t-butoxycarbonyl-2-methyl-4-piperidone (3.89 g, 18.24 mmol) dissolvedin THF (40 mL) was added via a cannula at −78° C. The reaction mixturewas stirred at −78° C. for 3 h. The reaction was then quenched with 75mL of saturated aqueous NaCl solution. The mixture was extracted with(1×75 mL, 2×125 mL) EtOAc. The combined organic layers were dried overCaCl₂ and filtered. The filtrate was concentrated and purified by mediumpressure chromatography (30% Et₂O/hexanes) to give the intermediatetitle compound as a yellow foam (1.798 g, 26%). IR (KBr) 3009, 2978cm⁻¹. Ion Spray MS 378 (M+H)⁺; 436 (M+CH₃COO⁻)⁻.

Preparation 4

[0055] Preparation ofN-t-Butoxycarbonyl-4-hydroxy-4-(6-methylbenzo[b]thiophen-2-yl)piperidine.

[0056] To a solution of 6-methylbenzo[b]thiophene (1.25 g, 8.43 mmol) indry THF (20 mL) at −78° C. was added 1.6 M n-BuLi in hexanes (6.32 mL,10.1 mmol). The solution was stirred at −78° C. for 40 min.1-t-Butoxycarbonyl-4-piperidone (1.84 g, 9.27 mmol) dissolved in THF (10mL) was added via a cannula at −78° C. The reaction mixture was stirredat −78° C. for 3 h. The reaction was then quenched with 50 mL of water.The mixture was extracted (3×75 mL) with EtOAc. The combined organiclayers were dried over MgSO₄ and filtered. The filtrate was concentratedto an oil and allowed to stand 3 days in which time the materialcrystallized. The crystals were rinsed with a mixture of EtOAc/hexanesto give the intermediate title compound as yellow crystals (2.13 g,72.6%). IR (KBr) 1681, 1429, 1246 cm⁻¹. FD+MS 347.0 (M).

Preparation 5

[0057] Preparation ofN-t-Butoxycarbonyl-4-hvdroxy-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine.

[0058] To a solution of 6-methylbenzo[b]thiophene (6.11 g, 41.21 mmol)in dry THF (90 mL) at −78° C. was added 1.6 M n-BuLi in hexanes (30.9mL, 49.4 mmol). The solution was stirred at −78° C. for 40 min. TheN-t-butoxycarbonyl-2-methyl4-piperdone (5.27 g, 24.7 mmol) dissolved inTHF (47 mL) was added via a cannula at −78° C. The reaction mixture wasstirred at −78° C. for 3 h. The reaction was then quenched with 200 mLof water. The mixture was extracted (3×200 mL) with EtOAc. The combinedorganic layers were dried over MgSO₄ and filtered. The filtrate wasconcentrated and run through a column of silica gel (17% EtOAc/hexanes)to give the intermediate title compound with some unreactedN-t-butoxycarbonyl-2-methyl-4-piperidone as an orange oil (6.75 g, 45%).IR (KBr) 1680, 1418, 1366, 1158 cm⁻¹. Ion Spray MS 420 (M+CH₃COO⁻)⁻.

Preparation 6

[0059] Preparation ofN-t-Butoxycarbonyl-4-(8-methoxynaphth-2-yl)-4-piperidinol.

[0060] To a solution of 7-bromo-1-methoxynaphthalene (1.50 g, 6.33 mmol)in dry THF (30 mL) at −78° C. was added 1.6 M n-BuLi in hexanes (4.35mL, 6.96 mmol). The solution was stirred at −78° C. for 15 min.N-t-Butoxycarbonyl-4-piperidone (1.51 g, 7.59 mmol) dissolved in THF (10mL) was added via a cannula at −78° C. The reaction mixture was stirredat −78° C. for 2.5 h. The reaction was then quenched with 30 mL ofsaturated aqueous NH₄Cl solution. The mixture was extracted (2×150 mL)with EtOAc. The combined organic layers were then dried over MgSO₄ andfiltered. The filtrate was concentrated and purified by silica gelchromatography (25% EtOAc/hexanes) to give the intermediate titlecompound as a white foam (1.42 g, 63%). IR (CHCl₃) 3350 (br), 1681 cm⁻¹.Ion Spray MS 358 (M+H)⁺; 240 (M-117(-(Boc+H₂O)))⁺; 430 (M+CH₃COO⁻)⁻.¹HNMR (CDCl₃) δ 8.31 (d, J=2.0 Hz, 1H), 779 (d, J=8.3 Hz, 1H), 7.60 (dd,J=8.8, 2.0 Hz, 1H), 7.34-7.40 (m, 2H), 6.81 (dd, J=7.1, 2.0 Hz, 1H),4.03-4.06 (br m, 2H), 3.99 (s, 3H), 3.29 (br dt, J=13.0, 2.4 Hz, 2H),2.12 (dt, J=13.0, 4.9 Hz, 2H), 1.79-1.83 (br m, 2H), 1.61 (br s, 1H),1.48 (s, 9H).

Preparation 7

[0061] Preparation of1-(t-Butyloxycarbonyl)-4-(6-methoxynaphth-2-yl)-2-methylpiperidin-4-ol.

[0062] Scheme I, step A: To a solution of 2-bromo-6-methoxynaphthalene(13.009 g, 54.9 mmol) in tetrahydrofuran (400 mL) at −78° C. was addeddropwise t-butyllithium (71.0 mL, 0.121 mol). After 30 minutes at −78°C., a solution of 1-(t-butyloxycarbonyl)-2-methyl-4-piperidone (12.87 g,60.4 mmol) in tetrahydrofuran (50 mL) was added dropwise. The mixturewas stirred at −78° C. for 4 hours and then diluted with saturatedammonium chloride and extracted 3 times with ethyl acetate. The combinedorganic layers were dried over sodium sulfate, filtered and evaporated.The residue was purified by silica gel chromatography(dichloromethane/2% methanol in dichloromethane gradient eluent) to give5.81 g (29%) of the title compound as a yellow oil. FDMS m/e=362 (M⁺+1).

Preparation 8

[0063] Preparation ofN-t-Butoxycarbonyl-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol.

[0064] Preparation of(±)-N,N-Dimethyl-2-(2-ethylphenyl)-2-hydroxythioacetamide.

[0065] A solution of 30.11 g of 1-bromo-2-ethylbenzene in ca. 500 mL offreshly distilled THF was treated with 112 mL of 1.6 M n-BuLi in hexanesat −78° C. over a period of ca. 3 h. To this was added 15 mL ofanhydrous DMF, and the mixture was stirred at −78° C. for 30 min. Thecold bath was removed, and the reaction was quenched with ca. 300 mL ofsaturated aqueous NH₄Cl. The layers were 2S separated, and the organiclayer was washed with ca. 300 mL of brine. The aqueous layers were backextracted with 2×500 mL of EtOAc. Combined organic layers were driedover MgSO₄, concentrated, and dried under house vacuum to yield 20.89 g(96%) of fairly clean crude 2-ethylbenzaldehyde.

[0066] To 290 mL of diisopropylamide in ca. 500 mL of freshly distilledTHF at −70° C. was added 117 mL of 1.6 M n-BuLi in hexanes, and theyellow solution was stirred at −70° C. for 20 min, for 15 min withoutthe cold bath, then re-cooled to −73° C. To this was added a pre-cooled(−70° C.) mixture of 20.89 g of the crude benzaldehyde and 16 mL ofN,N-dimethylthioformamide in 70 mL of freshly distilled THF via acannula over 15 min. The reddish clear solution was stirred at −75° C.for 45 min, then the cold bath was removed, and the mixture was stirredfor another 30 min. The reaction was quenched with ca. 300 mL ofsaturated aqueous NH₄Cl, and the layers were separated. The aqueouslayer was extracted with 3×500 mL of EtOAc. The organic layers werewashed with ca. 300 mL of brine, combined, dried over MgSO₄, andconcentrated. The residue was crystallized from EtOAc-hexanes to afford25.20 g (73%) of yellowish crystalline solid. IR (CHCl₃) ˜3200 (br),3009, 1529, 1387 cm⁻¹. mp 104-105° C. Ion Spray MS 223.9 (M+H)⁺.C₁₂H₁₇NOS analysis: Calculated found C 64.54 64.70 H 7.67 7.73 N 6.276.31

[0067] Preparation of 4-Ethyl-2-(N,N-dimethylamino)benzo[b]thiophene.

[0068] N,N-Dimethyl-2-(2-ethylphenyl)-2-hydroxythioacetamide (25.1 g,112 mmol) was dissolved in Eaton's reagent (7.5% w/w P₂O₅/MeSO₃H) (330mL). The reaction mixture was heated to 80° C. and stirred for 1 h. Thereaction mixture was then cooled to room temperature and stirred for anadditional 1.5 h. The reaction was quenched by pouring the reactionmixture slowly into cooled (0° C.) 5.0 N NaOH (1.60 L). The mixture wasextracted with EtOAc (2×1.50 L). The combined organic layers were thendried over MgSO₄ and concentrated to yield the title benzo[b]thiophene(21.66 g, 94% crude yield) as a red oil. EIMS 205 M⁺; 190 (M-15)⁺(basepeak).

[0069]¹HNMR (CDCl₃) δ 7.42 (d, J=7.8 Hz, 1H), 7.04 (d, J=7.3 Hz, 1H),6.98 (t, J=7.6 Hz, 1H), 5.98 (s, 1H), 3.01 (s, 6H), 2.82 (q, J=7.8 Hz,2H), 1.30 (t, J=7.8 Hz, 3H).

[0070] Preparation of 4-Etylthianapthen-2-one.

[0071] 4-ethyl-2-dimethylaminobenzo[b]thiophene (11.10 g, 54.0 mmol) wasdissolved in a 1:1 mixture of THF/1.0 N HCl (380 mL). The biphasicmixture was stirred vigorously and heated at reflux for 3 h 15 min. Thereaction mixture was then cooled to room temperature and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×400 mL). Thecombined organic layers were dried over MgSO₄ and concentrated to give4-ethylthianapthen-2-one (9.63 g, quantitative crude yield) as a darkred solid.

[0072]¹HNMR (CDCl₃) δ 7.19 (t, J=7.8 Hz, 1H), 7.11 (d, J=6.8 Hz, 1H),7.00 (d, J=7.3 Hz, 1H), 3.82 (s, 2H), 2.51 (q, J=7.8 Hz, 2H), 1.17 (t,J=7.8 Hz, 3H).

[0073] Preparation of 4-Ethylbenzo[b]thiophene.

[0074] To a solution of 4-ethylthianapthen-2-one (19.5 g, 110 mmol) inCH₂Cl₂ (1.15 L) was added dropwise 1.0 M diisobutylaluminum hydride intoluene (150 mL, 150 mmol) at 0° C. The solution was stirred at 0° C.for 2 h. The reaction was quenched with conc. HCl (700 mL) addeddropwise over a period of 1.5 h. This mixture was then stirredvigorously for 2 h. The layers were separated, and the organic layer waswashed with brine (1×500 mL), dried over MgSO₄ and concentrated. Theresidue was purified by medium pressure chromatography (100% hexanes) togive 4-ethylbenzo[b]thiophene as a yellow oil (6.37 g, 37%). EIMS 162M⁺.

[0075]¹HNMR (CDCl₃) δ 7.53 (d, J=7.8 Hz, 1H), 7.09 (t, J 7.8 Hz, 1H),7.05 (d, J=6.4 Hz, 1H), 6.98 (distorted d, 2H), 2.80 (q, J=7.8 Hz, 2H),1.15 (t, J=7.8 Hz, 3H).

[0076] Preparation ofN-t-Butoxycarbonyl-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol.

[0077] To a solution of 4-ethylbenzo[b]thiophene (6.37 g, 39.2 mmol) indry THF (200 mL) at −78° C. was added 1.6 M n-BuLi in hexanes (27.0 mL,43.2 mmol). The solution was stirred at −78° C. for 2 h.N-t-Butoxycarbonyl-2-methyl-4-piperidone (6.70 g, 31.4 mmol) dissolvedin THF (20 mL) was added via a cannula at −78° C. The reaction mixturewas stirred at −78° C. for 3 h. The reaction was then quenched with 200mL of saturated aqueous NH₄Cl solution. The mixture was extracted withEtOAc (1×200 mL). The combined organic layers were then dried over MgSO₄and filtered. The filtrate was concentrated and purified by mediumpressure chromatography (20% EtOAc/hexanes) to give the final titlecompound,N-t-butoxycarbonyl-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methyl-4-piperidinolas a white foam (6.58 g, 56%). IR (CHCl₃) 3425 (br), 1664, 1692 cm⁻¹.Ion Spray MS 376 (M+H)⁺; 302 (M-73)⁺ (base peak); 434 (M+CH₃COO⁻)⁻.C₂₁H₂₉NO₃S

EXAMPLE 1

[0078] Preparation of 4-(3-Methylbenzo[b]thiophen-5-yl)-piperidinehydrochloride.

[0079] Scheme I, Step C: To a solution of1-(t-butyloxycarbonyl)-4-(3-methyl-1-trimethylsilylbenzo[b]thiophen-5-yl)-piperidin-4-ol(458 g, 1.09 mol, from preparation 2) in CH₂Cl₂ (4.6 L) was added 871 mL(5.46 mol, 5.0 equiv) of triethylsilane. The mixture was cooled to −30°C. and 420 mL of trifluoroacetic acid (5.45 mol, 5.0 equiv) was addeddropwise to the solution over 35 minutes. The mixture was stirred for2.5 hours while gradually warming to 13° C. An additional 420 mL oftrifluoroacetic acid was added over 15 minutes. After warming to roomtemperature over 3.5 hours, ice (6 L), water (5 L), and concentratedaqueous NaOH (628 mL, 12.0 mol, 11.0 eq) were added. The layers wereseparated and the aqueous layer was extracted with two 1.5 L portions ofCH₂Cl₂. The organic layers were combined, dried (NaSO₄), andconcentrated under vacuum to give a clear, colorless oil, which wasredissolved in 4 L of ether. The hydrochloride salt was formed bydropwise addition of a solution of HCl in EtOAc (245 mL) until theslurry pH measured 2-3. The resulting slurry was stirred for 2 hours,filtered, rinsed with ether, and dried overnight in a vacuum oven at 45°C. to give 271 g of white crystalline4-(3-methylbenzo[b]thiophen-5-yl)-piperidine hydrochloride (92.8%yield).

[0080]¹H NMR (500 MHz, DMSO) δ 2.10-2.20 (m, 2), 2.30 (q, 2), 2.42 (s,3), 2.93 (m, 1), 3.0-3.10 (m, 2), 7.09 (s, 1), 7.25 (d, 1), 7.57 (s, 1),7.80 (d, 1); ¹³C NMR (75 MHz, DMSO) δ 13.5, 29.6, 38.9, 43.4, 119.3,122.7, 122.9, 123.2, 131.5, 137.7, 139.6, 140.9. Anal. Calcd forC₁₄H₁₈CINS: C, 62.79; H, 6.77; N, 5.23. Found: C, 62.66; H, 6.65; N,5.24.

EXAMPLE 2

[0081] Preparation of1-(t-butyloxycarbonyl)-4-(3-Methylbenzo[b]thiophen-5-yl)-piperidinehydrochloride.

[0082] Scheme I, Step A: To a solution of1-(t-butyloxycarbonyl)-4-(3-methyl-1-trimethylsilylbenzo[b]thiophen-5-yl)-piperidin-4-ol(458 g, 1.09 mol, from preparation 2) in CH₂Cl₂ (4.6 L) is added 871 mL(5.46 mol, 5.0 equiv) of triethylsilane. The mixture is cooled to −30°C. and 420 mL of trifluoroacetic acid (5.45 mol, 5.0 equiv) is addeddropwise to the solution over 35 minutes. The mixture is stirred for 1hour while gradually warming to 5° C. Then ice (6 L), water (5 L), andconcentrated aqueous NaOH (314 mL, 6.0 mol, 5.5 eq) are added. Thelayers are separated and the aqueous layer is extracted with two 1.5 Lportions of CH₂Cl₂. The organic layers are combined, dried (Na₂SO₄), andconcentrated under vacuum to provide the title compound.

EXAMPLE 3

[0083] Preparation of4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine HCl.

[0084] Scheme I, step C: The title compound is prepared from(±)N-t-butoxycarbonyl-4-hydroxy-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine(prepared in preparation 3) in a manner analogous to the proceduredescribed in Example 1.

EXAMPLE 4

[0085] 25 Preparation of (±)N-t-Butoxycarbonyl-4-(6-methoxybenzo[b]thiophen-2-vl)-2-methylpiperidine.

[0086] Scheme I, step A: The title compound is prepared from(±)N-t-butoxycarbonyl-4-hydroxy-4-(6-methoxybenzo[b]thiophen-2-yl)-2-methylpiperidine(prepared in preparation 3) in a manner analogous to the proceduredescribed in Example 2.

EXAMPLE 5

[0087] Preparation of 4-(6-methylbenzo[b]thiophen-2-yl)piperidine HCl.

[0088] Scheme I, step C: The title compound is prepared fromN-t-butoxycarbonyl-4-hydroxy-4-(6-methylbenzo[b]thiophen-2-yl)piperidine(prepared in preparation 4) in a manner analogous to the proceduredescribed in Example 1.

EXAMPLE 6

[0089] Preparation ofN-t-Butoxycarbonyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine.

[0090] Scheme I, step A: The title compound is prepared fromN-t-butoxycarbonyl-4-hydroxy4-(6-methylbenzo[b]thiophen-2-yl)piperidine(prepared in preparation 4) in a manner analogous to the proceduredescribed in Example 2.

EXAMPLE 7

[0091] Preparation of2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine HCl.

[0092] Scheme I, step C: The title compound is prepared fromN-t-butoxycarbonyl-4-hydroxy-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine(prepared in preparation 5) in a manner analogous to the proceduredescribed in Example 1.

EXAMPLE 8

[0093] Preparation ofN-t-Butoxycarbonyl-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine.

[0094] Scheme I, step A: The title compound is prepared fromN-t-butoxycarbonyl-4-hydroxy-2-methyl-4-(6-methylbenzo[b]thiophen-2-yl)piperidine(prepared in preparation 5) in a manner analogous to the proceduredescribed in

Example 2 EXAMPLE 9

[0095] Preparation of 4-(8-methoxynaphth-2-yl)piperidine HCl.

[0096] Scheme I, step C: The title compound is prepared fromN-t-butoxycarbonyl-4-(8-methoxynaphth-2-yl)-4-piperidinol (prepared inpreparation 6) in a manner analogous to the procedure described inExample 1.

EXAMPLE 10

[0097] Preparation ofN-t-Butoxycarbonyl-4-(8-methoxynaphth-2-vl)piperidine.

[0098] Scheme I, step A: The title compound is prepared fromN-t-butoxycarbonyl-4-(8-methoxynaphth-2-yl)-4-piperidinol (prepared inpreparation 6) in a manner analogous to the procedure described inExample 2.

EXAMPLE 11

[0099] Preparation of 4-(6-methoxynaphth-2-yl)-2-methylpiperidine HCl.

[0100] Scheme I, step C: The title compound is prepared from1-(t-butyloxycarbonyl)-4-(6-methoxynaphth-2-yl)-2-methylpiperidin-4-ol(prepared in preparation 7) in a manner analogous to the proceduredescribed in Example 1.

EXAMPLE 12

[0101] Preparation of1-(t-Butyloxycarbonyl)-4-(6-methoxynaphth-2-vl)-2-methylpiperidine.

[0102] Scheme I, step A: The title compound is prepared from1-(t-butyloxycarbonyl)-4-(6-methoxynaphth-2-yl)-2-methylpiperidin-4-ol(prepared in preparation 7) in a manner analogous to the proceduredescribed in Example 2.

EXAMPLE 13

[0103] Preparation of4-(4-ethylbenzo[b]thiophen-2-yl)-2-methylpiperidine HCl.

[0104] Scheme I, step C: The title compound is prepared fromN-t-butoxycarbony-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(prepared in preparation 8) in a manner analogous to the proceduredescribed in Example 1.

EXAMPLE 14

[0105] Preparation ofN-t-Butoxycarbonyl-4-(4-ethylbenzo[b]thiophen-2-vl)-2-methylpiperidine.

[0106] Scheme I, step A: The title compound is prepared fromN-t-butoxycarbonyl-4-(4-ethylbenzo[b]thiophen-2-yl)-2-methyl-4-piperidinol(prepared in preparation 8) in a manner analogous to the proceduredescribed in Example 2.

EXAMPLE 15

[0107] Preparation of 4-(4-Methoxybenzo[b]thiophen-2-yl)-piperidine HCl.

[0108] Scheme I, step C: The title compound was prepared fromN-t-butoxycarbonyl-4-(4-methoxybenzo[b]thiophen-2-yl)-4-piperidinol in amanner analogous to the procedure described in Example 1.

EXAMPLE 16

[0109] Preparation ofN-t-Butoxycarbonyl-4-(4-methoxybenzo[b]thiophen-2-yl)-piperidine.

[0110] Scheme I, step A: The title compound is prepared fromN-t-butoxycarbonyl-4-hydroxy-4-(4-methoxybenzo[b]thiophen-2-yl)-piperidinein a manner analogous to the procedure described in Example 2.

We claim:
 1. A process for preparing a reduced N-protected aminecompound comprising reducing an N-protected amine possessing a secondaryor tertiary alcohol with triethylsilane and trifluoroacetic acid.
 2. Theprocess according to claim 1 wherein the N-protected amine is anN-protected-4-substituted piperidine possessing a tertiary alcohol atthe 4-position of the piperidine ring.
 3. The process according to claim2 wherein the N-protecting group on the amine is an acid labile nitrogenprotecting group.
 4. The process according to claim 3 wherein the acidlabile nitrogen protecting group is a t-butyloxycarbonyl.
 5. The processaccording to claim 4 wherein the piperidine has a heterocycle,substituted heterocycle, substituted alkenyl or substituted aryl at the4-position wherein the substituted heterocycle, substituted alkenyl orsubstituted aryl are substituted with from 1 to 3 suitable activatinggroups.
 6. A process for preparing a compound of formula I:

wherein Pg represents a suitable nitrogen protecting group; X representsa heterocycle, substituted heterocycle, substituted alkenyl orsubstituted aryl wherein the substituted heterocycle, substitutedalkenyl or substituted aryl are substituted with from 1 to 3 suitableactivating groups; and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ eachindependently represent an alkyl, alkenyl, cycloalkyl, aryl, substitutedaryl, heterocycle, or substituted heterocycle, comprising treating acompound of formula II:

wherein the substituents are defined as above, with triethylsilane andtrifluoroacetic acid.
 7. The process according to claim 6 wherein Pg isan acid labile nitrogen protecting group.
 8. The process according toclaim 7 wherein the acid labile nitrogen protecting group is at-butoxycarbonyl.
 9. The process according to claim 8 wherein R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, and R⁸ each independently represent hydrogen orC₁-C₄ alkyl.
 10. The process according to claim 9 wherein R¹, R², R³,R⁴, R⁵, R⁶, R⁷, and R⁸ each independently represent hydrogen or methyl.11. A process for preparing a compound of formula Ia:

wherein X represents a heterocycle, substituted heterocycle, substitutedalkenyl or substituted aryl wherein the substituted heterocycle,substituted alkenyl or substituted aryl are substituted with from 1 to 3suitable activating groups; and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ eachindependently represent an alkyl, alkenyl, cycloalkyl, aryl, substitutedaryl, heterocycle, or substituted heterocycle, comprising treating acompound of formula II:

wherein Pg represents a suitable nitrogen protecting group and theremaining substituents are defined as above, with triethylsilane andexcess trifluoroacetic acid.